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Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses.
Wei SH, Rosen H, Matheu MP, Sanna MG, Wang SK, Jo E, Wong CH, Parker I, Cahalan MD
Nat Immunol 2005 Dec 6(12):1228-35 [abstract on PubMed] [related articles] [order article]
Selected by | Steve Ward / Benjamin Cravatt
First evaluation 10 Jan 2006 | Latest evaluation 12 Jan 2006
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Faculty Comments
Faculty Member Comments
Steve Ward
University of Bath, United Kingdom

This is an elegant and thought-provoking paper that proposes a novel model for sphingosine-1 phosphate receptor (S1P1)-mediated inhibition of T cell egress in lymphoid tissue. Imaging of T cells in explanted lymph nodes after treatment with S1P1 agonists revealed a marked reduction of T cell migration in the lymph node medulla. This could be reversed by washout of the S1P1 agonist or addition of S1P1 antagonists, such that medullar migration and sinus entry was restored. The authors interpret their data as evidence for the existence of endothelial gates (which are closed by S1P1 agonists) through which lymphocytes pass. This work does not provide definitive evidence for endothelial gates and key questions remain unanswered; however, it certainly provides an interesting alternative view to the popular notion that S1P1 agonists cause sequestration of lymphocytes due to internalisation of the receptors.

Evaluated 12 Jan 2006
Benjamin Cravatt
The Scripps Research Institute, United States of America

New Finding
This paper describes the application of innovative chemical and cell biology tools to delineate the mechanism of action of sphingosine 1-phosphate (S1P) receptors in lymphocyte transendothelial migration. Previous genetic studies had suggested that agonists of S1P receptors might inhibit lymophocyte egress by acting as 'functional antagonists' (i.e. downregulating these receptors). However, here, the authors show, through the use of two-photon imaging of lymphocyte movement in explanted lymph nodes, that S1P agonists cause a rapid block of T cell migration that can be reversed by agonist removal or the inclusion of an S1P receptor antagonist. These data suggest that S1P agonism, rather than functional antagonism, is the cause of blockade of lymphocyte egress. The authors propose a novel and provocative model for S1P agonist function whereby these reagents act on receptors expressed in endothelial cells (rather than lymphocytes) to inhibit lymphocyte egress. These studies also have important biomedical implications, as S1P receptors agonists may serve as useful immunosuppressant drugs.

Evaluated 10 Jan 2006
Faculty Comments

How to cite the Faculty of 1000 Biology evaluation(s) for this paper

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Steve Ward: Faculty of 1000 Biology, 12 Jan 2006 http://www.facultyof1000.com/article/16273098/evaluation

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